Fine-Tuning Deep Brian Stimulation

When the electrode has been implanted deep in the brain, and the stimulator is turned on for the first time, the results often appear miraculous. The tremors of Parkinson's disease suddenly stop. A profoundly depressed woman describes feeling as though she's rising out of a deep pit.

The technique, known as deep-brain stimulation (DBS), produces dramatic results so often that it is being tested as a treatment for obsessive-compulsive disorder, epilepsy, tics, chronic pain, dystonia, addiction, Alzheimer's disease, and even obesity. Yet even though electrodes have been implanted in more than 100,000 patients, the mechanism that makes DBS work remains a bit mysterious.

Until recently, the effectiveness of DBS was assumed to depend on stimulating a specific spot of brain tissue. But as advances in neuroimaging reveal the wiring of the brain in greater detail, it appears that DBS works by altering signals that flow among various brain regions.

"Depression is a disorder of circuits," says Helen Mayberg at Emory University, a pioneer in the use of DBS and a member of the Dana Alliance for Brain Initiatives. Mayberg has long recognized that deep depression somehow involves Brodmann area 25, a spot of tissue located between the eyes several inches behind the forehead. Area 25, also known as the subgenual cingulate, appears to be hyperactive in people with depression. In 2005, she and colleagues published a paper in Neuron describing how electrical stimulation of that area relieved intractable depression in six patients.

The stimulation produced erratic results, however; only four of the six achieved sustained remission of their depression. In subsequent cases, DBS produced immediate and dramatic relief in some patients while others improved little, if at all. Closer investigation of the fiber tracts (the white matter connections in the brain) has helped Mayberg recognize that relief depends not on the stimulation of area 25 itself, but on how effectively the electrical stimulation travels to other brain regions. Since fiber tracts vary from person to person, positioning the electrode in precisely the same spot in area 25 would not help all of them.

"Surgeons love to look at an atlas, make measurements, and drive to the same spot every time," Mayberg said during a presentation at the recent Society for Neuroscience annual meeting in San Diego. "We do exquisitely well at putting the electrode in the same place, but it has little bearing on whether a patient gets better or not. Responders look same as non-responders. The devil is in the details of each individual." Producing relief still depends on putting the electrode in precisely the right place, Mayberg says, but the right place varies slightly from patient to patient.

For example, the hyperactivity in area 25 found in severely depressed people often is accompanied by reduced activity in the frontal cortex. Delivering electrical stimulation that flows from area 25 to the frontal cortex appears be key to providing relief.

"This is not just about changing activity in area 25," Mayberg said. "This is also about changing activity remote from the target."

But brain regions are massively interconnected, and stimulation of area 25 may travel to regions involved with attention, emotion, cognition, and rumination, depending on the arrangement of the person's fiber tracts. To help anticipate those pathways, Mayberg and her colleagues produce a "probabilistic tract map" for each patient, predicting where the electrical current will travel. A 1 millimeter alteration in the placement of a contact can make all the difference.

Based on these findings Mayberg has asked certain patients to return to the operating room so surgeons can reposition the contacts, sometimes by just a millimeter or two. One woman with severe depression had improved by about 30 percent after her initial DBS surgery. "She was better, but not better enough," Mayberg said. "We went back and found that the insertion on the left side wasn't deep enough. We moved it two millimeters, and that was the difference between suffering and remission for her."

DBS also is being used to treat intractable obsessive-compulsive disorder, which can consume its victims with unwanted thoughts and urges. A video shown at the Society for Neuroscience meeting showed a young man who moved in slow motion "because he was fearful he would do the wrong thing and condemn his parents to hell, even though he knew these thoughts were irrational," explained Benjamin Greenberg of Brown University and Butler Hospital in Providence, Rhode Island. "He also wound up not speaking for 18 months because he feared he would say the wrong thing. And because of his rituals involving food he lost a lot of weight, and was kept alive on a liquid diet."

DBS can help about half of such patients achieve considerable relief from their obsessive thoughts and compulsive urges, Greenberg said. The results are variable, but he too thinks that mapping brain circuits affected by electrical stimulation will improve results. He is leading a clinical trial sponsored by the National Institute of Mental Health that will involve up to 30 people with OCD, who will all receive brain implants. Half will start receiving DBS right away, and the other half will receive "sham" stimulation first, to determine if the surgery itself produces a placebo effect. Later their stimulator will be turned on. The study, along with related work by a team of scientists, will provide "a window into mechanism of action" of DBS in OCD, Greenberg said.

DBS has also been used to treat tics that often accompany Tourette syndrome, said Kendall H. Lee, a neurosurgeon at the Mayo Clinic in Rochester, MN. He showed a video of an adolescent boy with a tic that caused him to twist his head so violently to the side that he suffered a stress fracture in his vertebrae. After surgery to implant a DBS stimulator in the thalamic nuclei, the tic disappeared.

Five people with Tourette syndrome have been treated with DBS, Lee said. He thinks that DBS to the thalamic nuclei stimulates the release of adenosine, an inhibitory neuromodulator. "Adenosine dampens oscillations in the thalamus," he says. "We believe that's how we're able to stop tremors."

Now that researchers understand that DBS affects brain connections, the treatment will receive a big boost from the Human Connectome Project, said Cameron McIntyre at Case Western Reserve University School of Medicine.

"I think it's obvious how this will tie in," he said. "We need to understand [brain] pathways. What are they connected to? How do they vary from patient to patient? What are some of the imaging technologies we can use to enhance our understanding?"

Research into DBS also will benefit from funding from the federal Defense Advanced Research Projects Agency (DARPA), which has announced plans to invest $70 million over five years in the technology, aiming to help brain-injured combat veterans. Part of the research is to develop a feedback mechanism that could help modulate DBS stimulation and make it more effective.

Such goals may seem out of reach at present, but speaking of the progress of brain research, Lee invoked the words of one of his medical school professors: "Everyone overestimates where we'll be in 5 years, but underestimate where we'll be in 10."